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Gene Therapy for Huntington's Disease
Overview Huntington's disease is a hereditary neurodegenerative disease thats progresses into decreased cognitive function and changes in one's behavior (7). This is an autosomal dominant mutation. The wild-type gene produces a protein called "Huntingtin." This gene is called the HTT gene and is located on Chromosome 4 (1). Since this disease is a dominant disorder, it is a prime candidate for gene therapy. Gene therapy is designed to reduce gene expression of mutated genes that are detrimental to the organism, such as a mutated version of the HTT gene. Causes and Symptoms of Huntington's Disease The cause of Huntington's disease can be attributed to a trinucleotide repeat, specifically CAG, within the HTT gene (1). This repeat can range anywhere from 36-120 nucleotides in length. The more repeats there are within the sequence, the more severe the phenotypic traits will be. Individuals who have 36-40 repeats show very mild symptoms, if any at all. The long repeats are translated into a longer version of the Huntingtin protein, which then undergoes proteolytic cleavage (1). The protein is cleaved into smaller fragments, which are toxic to neuronal cells. These fragments accumulate in neurons and disrupt function. Such functions include motor coordination, cognitive thinking and emotional control (2). Huntington's disease causes some very severe symptoms in individuals, such as hallucinations, psychosis, behavioral disturbances and restlessness. These symptoms generally are seen before symptoms that involve movement are seen. Individuals affected by Huntington's disease generally have a weak gait, abnormal facial movements, and rapid, uncontrollable jerking motions of the limbs. After the symptoms involving movement are seen, the dementia is usually what affects the individual next. Loss of memory, extreme confusion, personality changes, and loss of judgment are the main symptoms seen from the onset of dementia (2). HTT and Huntingtin The HTT gene is located on Chromosome 4, at 4p16.3 (1). The gene product of the HTT gene is the protein Huntingtin. The exact function of the Huntingtin protein is still unknown, except for that it plays a key role in the embryonic development and function of nerve cells. However, huntingtin is not just seen in the brain; this protein is found in all tissues throughout the body. The wild-type HTT gene contains a series of CAG repeats within it, generally 10-35 repeats are seen. Individuals with a higher number of CAG repeats have Huntington's disease and have the chance to pass this disorder to their offspring. As this mutated gene is passed down through generations, more repeats are added to this sequence. Adding more repeats will make each progressive generation have a stronger version of this disease (1). Gene Therapy Intervention There are, however, a few gene therapy techniques that are being researched to cure Huntington's disease, or to ease the symptoms at least. One technique was to target and silence the HTT gene. Silencing this gene will prevent the cells from producing the dysfunctional protein. This technique uses RNA interference to reduce the HTT gene's expression. RNA interference uses RNAi molecules that degrade selected mRNA molecules (in this case HTT transcripts), which in turn will prevent that translation into the Huntingtin protein (3,6). Another gene therapy technique uses siRNA to interfere with HTT gene production. siRNA molecules bind to the mutated gene, which blocks the transcription of the gene. These siRNA molecules were introduced via an adeno-associated viral vector. The vector contained a specific sequence that encodes specific siRNA that will bind to the mutated HTT gene to halt the production of the mutated Huntingtin protein. This technique was pioneered by Liz Stanek at Genzyme (3,5). References 1. HTT Gene. ''NIH 2. ''Huntington's Disease. ''NCBI 3. ''Novel RNAi therapy silences mutated Huntington's disease gene and reduces symptoms. Eurekalert 4. ''Gene Therapy for Huntington's Disease. ''ScienceDirect 5. ''Gene Therapy in Mouse Models of Huntington Disease. ''PMCID: PMC3131092 6. ''RNA Interference. ''Wikipedia 7. ''Huntington's Disease. ''Wikipedia